Ischemic stroke is a common cause of death and serious disability and is usually caused by a blockage in a blood vessel leading to or within the intracranial cavity and/or brain. Few effective treatments are available. One treatment consists of removing the blockage within the blood vessel in question. Other treatments consist of altering perfusion pressures within the brain by increasing blood pressure to the brain. Blockage of blood vessels can be removed using a range of mechanical devices, or using “clot busting agents” which are delivered intravenously or intra-arterially. Among such clot busting agents is Tissue plasminogen factor (tPA), a thrombolytic agent that is administered to some stroke subjects to dissolve emboli causing the ischemia and thus restore blood flow to the brain, and recombinant tPA's such as Alteplase, reteplase and tenecteplase. Other thrombolytic drugs that break down clots include streptokinase, urokinase and desmotaplase. Among mechanical reperfusion devices, there are intra-arterial catheters, balloons, stents, and various clot retrieval devices, such as the Penumbra System Reperfusion Cather. Among treatments that alter perfusion pressures in the brain are devices that increase the arterial pressure in the brain, such as balloons that can be inflated in the extra-cerebral arteries such as the aorta thereby diverting blood flow from other body areas and increasing brain arterial perfusion, such as the CoAxia NeuroFlow™ catheter device. Collectively, these strategies can be considered as medical and mechanical agents that enhance brain perfusion on or after the onset of cerebral ischemia (hereafter collectively “reperfusion therapies”).
Although tPA and other reperfusion therapies administered soon after onset of ischemia are effective in reducing death or disability from ischemic stroke, less than about 3% of subjects presenting with stroke are treated with tPA or other reperfusion therapies. The low usage of tPA and other reperfusion therapies is due in part to the risk of death if administered to a patient who is having or who is at an elevated risk for sustaining a brain hemorrhage. Stroke can be the result of ischemia or hemorrhage. Too often, the time required to bring a subject to a hospital, reach an initial diagnosis and perform a brain scan to distinguish between ischemic and hemorrhagic stroke would place a subject outside the window in which tPA or other reperfusion therapies can be effective. Thus, many ischemic stroke subjects, who could benefit from tPA or other reperfusion therapies, do not receive such treatment.
A different form of treatment for stroke and related conditions is now in clinical trials (see WO 2010144721 and Aarts et al., Science 298, 846-850 (2002)). This treatment uses Tat-NR2B9c (NA-1), an agent that inhibits PSD-95, thus disrupting binding to N-methyl-D-aspartate receptors (NMDARs) and neuronal nitric oxide synthases (nNOS) and reducing excitoxicity induced by cerebral ischemia. Treatment reduces infarction size and functional deficits.